The PI proposes to study the effects of mtDNA oxidative phosphorylation (OXPHOS) defects in two aspects of cancer. There are two main goals: First, determine the role of OXPHOS defects in cell growth and tumor development; and second, determine the role of OXPHOS defects in cell death. The background is that somatic mtDNA mutations have been described in many colorectal tumors. However, their role in tumor growth is not understood. He plans to use three colorectal cancer cell lines with mtDNA mutations as models to study the phenotypic consequence of mtDNA mutations. The mtDNA from these cell lines will be transferred to an osteosarcoma cell line without mtDNA, and the effects on mitochondrial function and cell growth will be assessed. The effects of these and other mtDNA mutations in OXPHOS on reactive oxygen species production, cell growth, and apoptosis in vitro and in vivo will be examined. In a second specific aim, he will study the effect of genetically determined mitochondrial dysfunction on apoptosis. Osteosarcoma cell lines with and without mtDNA will be used to examine the effects of low mitochondrial membrane potential and impaired OXPHOS on susceptibility to apoptosis. The effects of Bcl-XL and Bax expression in differing mtDNA contexts will also be examined.